1H-indazole-3-acetic acids as aldose reductase inhibitors

ABSTRACT

Abstract Certain 1H-indazole-3-acetic acid derivatives, and their pharmaceutically-acceptable esters and salts, are inhibitors of the aldose reductase enzyme, and so are useful in the treatment of diabetic complications.

This is a continuation of application Ser. No. 07/499,279, filed on Jun.11, 1990 now abandoned.

BACKGROUND OF THE INVENTION

The present invention is concerned with 1H-indazole-3-acetic acidderivatives and their pharmaceutically-acceptable esters and salts. Bymeans of their inhibition of the aldose reductase enzyme, thesecompounds are useful in the treatment of diabetic complications.

Compounds, such as sorbinil(S-6-fluorospiro[chroman-4,4'-imidazoline]-2',5'-dione; Sarges, U.S.Pat. No. 4,130,714), which have aldose reductase inhibitory activity,are of value in controlling certain chronic complications arising fromdiabetes mellitus (e.g., diabetic cataracts and neuropathy).

Non-hydantoin compounds previously reported to inhibit aldose reductaseinclude 1H-benz[d,e]isoquinoline-1,3(2H)-dione-2-acetic acidderivatives, Sestanj et al., U.S. Pat. No. 3,821,383; halogensubstituted chroman-4-carboxylic and chroman-4-acetic acids, Belletire,U.S. Pat. No. 4,210,663; spiro[chroman-4,5'-oxazolidin]-2',3'-diones,Schnur, U.S. Pat. No. 4,200,642; and variously substitutedphthalazin-1(2H)-on-4-acetic acids, Larson et al., published EuropeanPatent Application No. 222,576.

Variously substituted 1-benzyl-1H-indazole-3-carboxylic acids andspecifically 1-(p-chlorobenzyl)-1H-3-acetic acid have been reported tobe useful as antispermatogenic agents, Corsi et al., J. Med. Chem., vol19, pp. 778-783 (1976).

SUMMARY OF THE INVENTION

The present invention is directed to compounds having the formula##STR1## wherein X¹ and X² are each independently hydrogen, fluoro,chloro, bromo, trifluoromethyl, (C₁ -C₃)alkyl or (C₁ -C₃)alkoxy;

R is hydrogen or a radical group forming a conventional ester which ishydrolyzable under physiological conditions;

R¹ is ##STR2## Y is sulfur or oxygen; X³, when taken separately, ishydrogen, fluoro, chloro, bromo, trifluoromethyl, (C₁ -C₃)alkyl, (C₁-C₃)alkoxy or ##STR3## X⁴, when taken separately, X⁵ and X⁶ are eachindependently hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C₁-C₃)alkyl or (C₁ -C₃)alkoxy; and

X³ and X⁴, when taken together, are combined with the adjacent carbonsto which they are attached to form a benzene ring substituted by X⁵ andX⁶ ;

the pharmaceutically acceptable cationic salts thereof when R ishydrogen; and

the pharmaceutically acceptable acid addition salts thereof.

Esters of acidic pharmaceutical compounds (such as penicillins andnon-steroidal antiinflammatory agents) which are hydrolyzed underphysiological conditions (sometimes referred to as pro-drug esters) arebecoming as common as pharmaceutically acceptable salts in thepharmaceutical art. Of particular value in the present instance arethose esters wherein R is:

1H-furan-5-on-2-yl;

1H-isobenzofuran-2-on-7-yl;

gamma-butyrolacton-4-yl;

--CH₂ CH₂ NR² R³ ;

--CHR⁴ OCOR⁵ ; or

--CHR⁴ OCOOR⁶ ;

wherein

R² and R³, taken separately, are each independently (C₁ -C₄)alkyl; ortaken together with the nitrogen to which they are attached form apyrrolidine, piperidine or morpholine ring;

R⁴ is hydrogen or methyl;

R⁵ is (C₁ -C₆)alkyl, (C₁ -C₆)carboxyalkyl, carboxycyclohexyl orcarboxyphenyl; and

R⁶ is (C₁ -C₆)alkyl.

The expression "pharmaceutically acceptable acid addition salt" refersto addition salts with inorganic and organic acids such as (but notlimited to) HCl, HNO₃, H₂ SO₄, H₃ PO₄, CH₃ SO₃ H, CH₃ C₆ H₄ SO₃ H, CH₃COOH, fumaric acid, succinic acid and citric acid.

The expression "pharmaceutically acceptable cationic salt" refers tocarboxylate salts where the cation is such as (but not limited to)sodium, potassium, calcium, magnesium, ammonium or protonated benzathine(N,N'-di-benzylethylenediamine), choline, ethanolamine, diethanolamine,ethylenediamine, meglamine (N-methylglucamine), benethamine(N-benzylphenethylamine), piperazine or tromethamine(2-amino-2-hydroxymethyl-1,3-propanediol).

Because of their ease of preparation and valuable aldose reductaseinhibitory activity, more preferred compounds of the formula (I) have X¹as hydrogen or 5-chloro, X² as hydrogen, and R as ##STR4## Mostpreferred compounds have Y as sulfur; and X¹ as 5-chloro, X⁵ as hydrogenand X⁶ as 5-fluoro; X¹ X⁵ and X⁶ each as hydrogen; X¹ as 5-chloro, X⁵ ashydrogen and X⁶ as 5-trifluoromethyl; X¹ as 5-chloro, X⁵ as 5-fluoro andX⁶ as 7-fluoro; or X¹ as hydrogen, X⁵ as 5-fluoro and X⁶ as 7-fluoro.

The present invention is also directed to pharmaceutical compositionsfor the control of chronic diabetic complications in mammals whichcomprise a compound of the formula (I) in a pharmaceutically acceptablecarrier; and to a method of controlling chronic diabetic complicationswhich comprises administering to a mammal suffering from chronicdiabetes a chronic diabetic complication controlling amount of acompound of the formula (I).

A further subject of the present invention is a method of controllingchronic diabetic complications which comprises administering to a mammalsuffering from chronic diabetes a chronic diabetic complicationcontrolling amount of a compound of the formula ##STR5## wherein R, X¹,X², X³ and X⁴ are as defined above.

DETAILED DESCRIPTION OF THE INVENTION

The aldose reductase inhibiting compounds (I) and (II) of the presentinvention are readily prepared according to the following scheme, inwhich R' is R (as defined above), (C₁ -C₄)alkyl, phenyl or benzyl; R" isR¹ or --C₆ H₃ X³ X⁴ (both as defined above); and X is a leaving groupsusceptible to nucleophilic displacement: ##STR6##

The displacement of X in the compound R"CH₂ X to form a compound of theformula (II) is a typical nucleophilic displacement reaction, generallycarried out in a reaction inert solvent in the presence of a base. Forexample, the group X can be chloro, bromo, iodo, mesyl (--SO₃ CH₃) ortosyl. For best results, the reaction is carried out on the anionic formof the 1H-indazole, readily obtained in situ by the action of a strongbase on the free indazole. When R' is H, hydrous conditions aresatisfactory, such that even KOH or NaOH are useful for this purpose. Inthis case, at least 2 molar equivalents (and usually an excess, e.g.,3-molar equivalents) of base are used, in order to form the dianion andassure selective reaction at nitrogen. However, when R is a radicalforming an ester, anhydrous and (except when the solvent is R'OH)aprotic conditions are much preferred, so as to avoid undesiredhydrolysis and/or ester exchange. Thus, in the latter case, sodiumhydride (or where practical R'ONa) is the preferred base for priorformation of the anion. In this case, only one molar equivalent of thebase is required, with no more than modest excesses (e.g., 0.1 molarequivalent) generally employed. Solvent is not critical in thisnucleophilic displacement, except to generally avoid protic solventsother than R'OH (e.g., aqueous solvents are fully satisfactory when R'is H, methanolic solvents are satisfactory when R' is CH₃, etc.). In anycase, the solvent should be significantly less acidic than the indazoleso as to maintain the latter in anionic form. Temperature is likewisenot critical, e.g., temperature ranges of about 0°-100° C. are generallysatisfactory, temperatures at or near ambient being most convenient. Forexample, when X is bromo, the displacement will generally be completewithin 15-30 minutes using a modest molar excess of the organic bromideto force the reaction to completion. Of course, when X is chloro, moretime will be needed, while when X is iodo, less time will be needed. Ifdesired, when X is other than iodo, the displacement reaction can becatalyzed by use of up to a mol or more of an iodide salt (e.g., NaI,KI).

As used here and elsewhere herein, the expression "reaction-inertsolvent" refers to a solvent which does not interact with startingmaterial, reagents, intermediates or desired product in a manner whichadversely affects the yield of the desired product.

When R' corresponds to R as defined above, the desired product (I) or(II) is of course directly formed in the displacement reaction. On theother hand, when R' is (C₁ -C₄)alkyl, phenyl or benzyl, the ester willthen be conventionally hydrolyzed to form the compound of the formula(I) or (II) wherein R is hydrogen. Preferred are basic conditions, forexample, using at least one molar equivalent (and usually an excess) ofan aqueous alkali metal hydroxide, generally in the presence of areaction-inert, water miscible organic solvent to aid in solubilizingthe ester.

When in the product is (I) or (II) wherein R is hydrogen, and an esterhydrolyzable under physiological conditions is desired, such esters arealso prepared according to usual methods. Thus when R is --CH₂ CH₂ NR²R³ the esters are readily prepared by reacting an activated form of theacid with a 2-(substituted-amino)ethanol of the formula ##STR7## Mixedanhydrides are well-suited as the activated form of the acid in suchpreparations. Generally, the acids are first converted in situ to atertiary amine salt in the presence of a 1 to 1.1 molar excess of theamine. A variety of tertiary amines are suitable for this purpose.Exemplary are triethylamine, N-methylpiperidine, N-methylmorpholine,dimethylaniline or quinoline. Suitable inert solvents are methylenechloride, chloroform, dimethylformamide, and dimethylacetamide. It ispreferrable that the acid be completely dissolved by the excess oftertiary amine, which may require a stirring period, together withgentle warming, if necessary. The solution of amine salt is then reactedwith an equivalent of alkyl (e.g. ethyl), benzyl, or phenylchloroformate, at a temperature in the range of -40° to 25° C.,preferably in the range -10° to 10° C., to form a mixed anhydride insolution. Without isolation, the mixed anhydride is reacted directlywith the appropriate alcohol of the formula (IV) to yield the desiredester. The reaction is usually initiated at a cool temperature (such as-40° to 15° C.), but allowed to warm to higher temperature (such as 15°to 40° C.) to complete the reaction. Alternatively, such esters areprepared by ester exchange, as specifically exemplified below. Thus, anintermediate ester of the formula (III) wherein R' is (C₁ -C₄)alkyl,phenyl or benzyl is reacted with an excess of the sodium salt of theamino alcohol (IV). The latter is generally formed in situ by reactionof the amino alcohol with NaH, in a reaction-inert solvent such astoluene, usually at a temperature in the range of 15°-85° C.

The esters wherein R is a conventional radical forming an ester which ishydrolyzable under physiological conditions are more generally preparedby reaction of a salt of the acid (I or II, R═H; preferably thetetrabutylammonium salt) with an appropriate compound containing adisplaceable halide (iodide, bromide or chloride; generally preferred,where available, in that order), or another group suitable fornucleophilic displacement. Exemplary are CH₃ OSO₂ CH₃, C₂ H₅ Br, CH₃ CH₂CH₂ I, ICHR⁴ OCOR⁵, ICHR⁴ OCOOR⁶, ##STR8## The required salt can be inisolated form, or more conveniently, formed in situ from the acid by useof at least one equivalent of a base. The reaction is carried out in areaction-inert solvent, preferably one which is essentially anhydrous. Aparticularly convenient reaction system employs excess potassiumcarbonate as base in acetone as solvent. When the halide is chloro orbromo, up to three or more equivalents of anhydrous sodium iodide isadded, if desired, to enhance the rate of reaction. An excess of thehalide reagent is not critical to the reaction, but such an excess willgenerally be used in order to force the reaction to completion in ashorter period of time. The rate of reaction will also depend greatly onthe halide (e.g., I>Br>Cl) and on the nature of the radical group R(e.g., more branched ICHCH₃ OCOCH₃ will react more slowly than ICH₂OCOCH₃). The reaction temperature is not critical, a temperature in therange of 0°-100° C. being generally satisfactory, but ambient or nearambient temperatures are preferred. Another preferred method convertsthe free acid form into the tetrabutylammonium salt, formed in water andextracted into an organic solvent such as chloroform, which is thenreacted with the organic halide. A typical procedure employing thelatter method is exemplified below.

By conventional modification of the isolation procedure, the compoundsof the formula (I) and (II) are alternatively isolated in the form of apharmaceutically-acceptable acid addition salt, as defined above. Suchsalts are also readily prepared from the isolated free base forms bystandard methods. For example, a molar equivalent of HCl, HBr, HNO₃ orsuccinic acid, or a half a molar equivalent of H₂ SO₄ or succinic acidis combined with the free base in an organic or aqueous solvent to formthe HCl, HBr, HNO₃, hemisuccinate, bisulfate or succinate salt,respectively. The salt is isolated by concentration and/or the additionof a non-solvent.

Similarly, by modification of the isolation procedure, the compounds ofthe formula (I) or (II) wherein R is H are alternatively isolated in theform of a pharmaceutically-acceptable cationic salt, as defined above.Such salts are also readily prepared from the isolated acid forms bystandard methods. For example, an equivalent of the correspondingcationic hydroxide, carbonate or bicarbonate, or of an amine, iscombined with the carboxylic acid in an organic or aqueous solvent. Thesalt is isolated by concentration and/or the addition of a non-solvent.

The 1H-indazole-3-acetic acids generally required as starting materialsfor synthesis of the compounds of the present invention are readilyavailable according to literature methods, for example, by chainextension of an extensive variety of 1H-indazole-3-carboxylic acidsdescribed in above cited Corsi et al., using the method also theredescribed: ##STR9## Corresponding (C₁ -C₄)alkyl, benzyl or phenyl1H-indazole-3-acetate esters are best prepared by conventional acidcatalyzed esterification, as exemplified in the preparations below. Thesame can be applied to the preparation of 1H-indazole-3-acetate estersof aminoethanols of the formula (IV), which are alternatively preparedby the ester exchange method exemplified below. It will be evident tothose skilled in the art that any such esters which are prepared viaactivated forms of the acid, or via nucleophilic displacement willgenerally require protection of the indazole nitrogen, e.g., by means ofa benzyloxycarbonyl group removable by hydrogenolysis once the estergroup is in place. As a practical matter, it is therefore usuallypreferred to introduce such ester groups after the benzyl orheteroarylmethyl group is already in place.

Variously substituted benzyl halides and heteroarylmethyl halides alsorequired as starting materials are also readily available, in many casescommercially, but in any event by conventional methods, for example,from corresponding carboxylate esters, carboxylic acids, aldehydes, andcarbinols, e.g. ##STR10##

The present compounds of the formulas (I) and (II), particularly intheir acid or salt form, are tested in vitro for their ability to reduceor inhibit aldose reductase enzyme activity, following the proceduredescribed in U.S. Pat. No. 3,821,383 and based on the procedure ofHayman et al., Journal of Biological Chemistry, 240, 877 (1965). Thesubstrate employed is partially purified aldose reductase enzymeobtained from human placenta. The results obtained with each compound ata concentration of 10⁻⁵ M or lower are expressed as percent inhibitionof enzyme activity, or, when tested at several concentration levels,expressed as an IC₅₀, the inhibition concentration calculated to show50% inhibition of enzyme activity.

The present compounds of the formulas (I) and (II) are tested in vivofor their ability to reduce or inhibit sorbitol accumulation in thesciatic nerve of streptozotocinized (i.e., diabetic) rats by a procedureessentially as described in U.S. Pat. No. 3,821,383. In the presentstudy, the amount of sorbitol accumulation in the sciatic nerves wasmeasured 27 hours after induction of diabetes. The compounds aregenerally administered orally at doses ranging from 2.5 to 100 mg/kg at4, 8 and 24 hours following the administration of streptozotocin. Theresults obtained in this manner are presented in terms of percentinhibition afforded by the test compound as compared to the case whereno compound was administered (i.e., the untreated animal where sorbitollevels normally rise from approximately 50-100 mM/g tissue to as high as400 mM/g tissue during the test period). In this test values below 20%are not always experimentally and statistically significant. Not all ofthe compounds of the present invention show in vivo activity by thisoral test. Such compounds will find parenteral or topical use asdescribed below.

The compounds of this invention are all readily adapted to therapeuticuse as aldose reductase inhibitors for the control of chronic diabeticcomplications in mammals. They are administered either orally orparenterally, or topically as eye drops, in dosages ranging from about0.1 to 10 mg/kg of body weight per day in single or divided doses. Ofcourse, in particular situations, at the discretion of the attendingphysician, doses outside of this range will be used.

The compounds of this invention can be administered in a wide variety ofdifferent dosage forms, i.e., they may be combined with variouspharmaceutically-acceptable inert carriers in the form of tablets,capsules, lozenges, troches, hard candies, powders, sprays, elixirs,syrups, injectable or eye drop solutions, and the like. Such carriersinclude solid diluents or fillers, sterile aqueous media and variousnon-toxic organic solvents.

For purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and calciumphosphate are employed along with various disintegrants such as starchand preferably potato or tapioca starch, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type are also employed as fillers in soft and hard-filledgelatin capsules; preferred materials in this connection also includelactose or milk sugar as well as high molecular weight polyethyleneglycols. When aqueous suspensions and/or elixirs are desired for oraladministration, the essential active ingredient therein can be combinedwith various sweetening agents, flavoring agents, coloring agents,emulsifying agents and/or suspending agents, as well as such diluents aswater, ethanol, propylene glycol, glycerin and various like combinationsthereof.

For purposes of parenteral administration, solutions in sesame or peanutoil or in aqueous propylene glycol can be employed, as well as sterileaqueous solutions of the corresponding water-soluble, alkali metal oralkaline-earth metal salts previously enumerated. Such aqueous solutionsshould be suitably buffered, if necessary, and the liquid diluent firstrendered isotonic with sufficient saline or glucose. These particularaqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous and intraperitoneal injection purposes. Inthis connection, the sterile aqueous media employed are all readilyobtainable by standard techniques well-known to those skilled in theart.

For purposes of topical administration, dilute, sterile, aqueoussolutions (usually in about 0.1% to 5% concentration), otherwise similarto the above parenteral solutions, are prepared in containers suitablefor dropwise administration to the eye.

The present invention is illustrated by the following examples. However,it should be understood that the invention is not limited to thespecific details of these examples.

EXAMPLE 1 1-[(benzothiazol-2-yl)methyl]-1H-indazole-3-acetic acid

To a vigorously stirring solution of 1H-indazole-3-acetic acid (0.88 g)in water (100 ml) containing sodium hydroxide (0.60 g) was added2-(bromomethyl)benzothiazole (1.25 g) and the resulting mixture heatedat 80° C. for 2.5 hours. The reaction solution was cooled to roomtemperature and extracted with ether (2×25 ml). The aqueous layer wascollected and acidified to a pH of about 4.0 with concentrated HCl, andthen extracted with ethyl acetate (2×20 ml). The organic layers werecombined, dried and evaporated to a yellow solid (yield: 0.67 g), whichwas crystallized from benzene (m.p. 164°-165° C.).

Substituting a molar equivalent of 5-chloro-1H-indazole-3-acetic acidfor 1H-indazole-3-acetic acid, the same method was employed to prepare:

1-(benzothiazol-2-yl)methyl-5-chloro-1H-indazole-3-acetic acid (m.p.213° C.).

Further substituting a molar equivalent of2-(bromomethyl)benzo[d]isothiazole, 2-(bromomethyl)benzoxazole or2-bromomethylquinoline for the 2-(bromomethyl)benzothiazole, the samemethod was used to prepare:

1-[(benzo[d]isothiazol-3-yl)methyl]-5-chloro-1H-indazole-3-acetic acid(m.p. 204°-205° C.);

1-[(benzoxazol-2-yl)methyl]-5-chloro-1H-indazole-3-acetic acid (m.p.194°-195° C.); and

1-[(2-quinolyl)methyl]-5-chloro-1H-indazole-3-acetic acid (m.p.201°-202° C.).

EXAMPLE 2 Methyl 1-(4-bromo-2-fluorobenzyl)-1H-indazole-3-acetate

To a solution obtained by adding sodium hydride (0.14 g; 50% w/wdispersion in mineral oil) to dimethylformamide (3 ml) containing methyl1H-indazole-3-acetate (0.45 g) was added 4-bromo-2-fluorobenzyl bromide(0.70 g). After 15 minutes, the reaction solution was poured onto icewater (20 ml). Sufficient 10% HCl was added to adjust the pH to about4.0 and the solution then extracted with ethyl acetate (2×20 ml). Thecombined organic extract was washed with water (2×20 ml), dried andevaporated. The residue was purified by chromatography on silica gel[yield: 0.31 g; ¹ H NMR (CDCl₃) 3.6 (s, 3H), 4.0 (s, 2H), 5.4 (s, 2H)6.8-7.2 (m, 6H), 7.6 (m, 1H)].

Substituting a molar equivalent of2-(bromomethyl)-5-(trifluoromethyl)benzothiazole,2-(bromomethyl)-5-fluorobenzothiazole, 2-(bromomethyl)benzothiophene,2-(bromomethyl)-5-(trifluoromethyl)benzoxazole or2-(bromomethyl)-5,7-difluorobenzthiazole, respectively for4-bromo-2-fluorobenzyl bromide, the same method was used to prepare:

methyl1-[(5-(trifluoromethyl)benzothiazol-2-yl)methyl]-1H-indazole-3-acetate[¹ H NMR (CDCl₃, 60 MHz): 3.65 (s, 3H), 4.0 (s, 2H), 5.9 (s, 2H),7.0-8.2 (m, 7H)];

methyl 1-[(5-fluorobenzothiazol-2-yl)methyl]-1H-indazole-3-acetate [¹ HNMR (CDCl₃, 60 MHz): 3.6 (s, 3H), 4.05 (s, 2H), 5.9 (s, 2H), 6.9-7.9 (m,7H)];

methyl 1-[(benzothien-2-yl)methyl]-1H-indazole-3-acetate [¹ H NMR(CDCl₃, 60 MHz): 3.65 (s, 3H), 4.05 (s, 2H), 4.65 (s, 2H), 7.0-7.8 (m,9H)];

methyl1-[(5-(trifluoromethyl)benzoxazol-2-yl)methyl]-1H-indazole-3-acetate [¹HNMR (CDCl₃, 60 MHz); 3.50 (s, 3H), 4.05 (s, 2H), 4.8 (s, 2H), 7.0-7.9(m, 7H)]; and

methyl 1-[(5,7-difluorobenzothiazol-2-yl)methyl]-1H-indazole-3-acetate[¹ HNMR (CDCl₃, 60 MHz);; 1.3 (t, J=8 Hz, 3H), 4.0 (s, 2H), 4.15 (q, J=8Hz, 2H), 5.9 (s, 2H), 6.9 (m, 1H), 7.2-7.7 (m, 5H).

Further substituting a molar equivalent of the corresponding ethyl esterfor methyl 1H-indazole-3-acetate, and a molar equivalent of2-(bromomethyl)-6-bromobenzothiazole, 2-(bromomethyl-5-chlorobenzoxazoleor 5-(bromomethyl)-3-(2-bromophenyl)-1,2,4-oxadiazole, respectively, for4-bromo-2-fluorobenzyl bromide, the same method was used to prepare:

ethyl 1-[(6-bromobenzothiazol-2-yl)methyl]-1H-indazole-3-acetate [¹ HNMRCDCl₃, 60 MHz): 1.25 (t, J=8 Hz, 3H), 4.05 (s, 2H), 4.2 (q, J=8 Hz, 2H),5.9 (s, 2H), 7.1-7.9 (m, 7H)];

ethyl 1-[(5-chlorobenzoxazol-2-yl)methyl]-1H-indazole-3-acetate [¹ HNMR(CDCl₃, 60 MHz): 11.2 (t, J=8 Hz, 3H), 4.0 (s, 2H), 4.1 (q, J=8 Hz, 2H),5.8 (s, 2H), 7.0-7.8 (m, 7H)]; and

ethyl1-[(3-(2-bromophenyl)-1,2,4-oxadiiazol-5-yl)methyl]-1H-indazole-3-acetate[¹ HNMR (CDCCl₃, 60 MHz): 1.2 (t, J=8 Hz, 3H), 4.0 (s, 2H), 4.2 (q, J=8Hz, 2H), 5.8 (s, 2H), 7.1-7.7 (m, 8H)].

Further substituting a molar equivalent of ethyl5-chloro-1H-indazole-3-acetate for the methyl 1H-indazole-3-acetate, and2-(bromomethyl)-5-bromobenzothiazole,2-(bromomethyl)-5-chlorobenzoxazole,2-(bromomethyl)-5-fluorobenzothiazole and2-(bromomethyl)-5-(trifluoromethyl)benzothiazole, respectively, for the4-bromo-2-fluorobenzyl bromide, the same method was used to prepare:

ethyl1-[(5-bromobenzothiazol-2-yl)methyl]-5-chloro-1H-indazole-3-acetate. ¹HNMR (CDCl₃, 60 MHz): 1.30 (t, J=8 Hz, 3H), 4.0 (s, 2H), 4.2 (q, J=8 Hz,2H), 5.85 (s, 2H), 7.1 (m, 4H), 7.6 (dd, J=2,7 Hz, 1H), 8.05 (d, J=2 Hz,1H)];

ethyl 1-[(5-chlorobenzoxazol-2-yl)methyl-5-chloro-1H-indazole-3-acetate[¹ HNMR (CDCl₃, 60 MHz): 1.25 (t, J=8 Hz, 3H), 3.95 (s, 2H), 4.1 (q, J=8Hz, 2H), 5.65 (s, 2H), 7.1 (m, 5H), 7.5 (m, 2H)];

ethyl 1-[(5-fluorobenzthiazol-2-yl)methyl-5-chloro-1H-indazole-3-acetate[¹ HNMR (CDCl₃, 60 MHz): 1.3 (t, J=8 Hz, 3H), 4.1 (s, 2H), 4.2 (q, J=8Hz, 2H), 5.95 (s, 2H), 7.1-7.9 (m, 6H)]; and

ethyl1-[(5-trifluoromethyl)benzothiazol-2-yl)methyl]-5-chloro-1H-indazole-3-acetate[¹ HNMR (CDCl₃, 60 MHz): 1.25 (t, J=8 Hz, 3H), 4.05 (s, 2H), 4.2 (q, J=8Hz, 2H), 5.9 (s, 2H), 7.1-8.2 (m, 6H)].

Further substituting a molar equivalent of methyl5-chloro-1H-indazole-3-acetate for the methyl 1H-indazole-3-acetate, and2-(bromomethyl)-5,7-difluorobenzothiazole for the 4-bromo-2-fluorobenzylbromide, the same method was used to prepare:

methyl5-chloro-1-[(5,7-difluorobenzothiazol-2-yl)methyl]-1H-indazole-3-acetate[m.p. 109°-112° C.].

EXAMPLE 3 1-(4-bromo-2-fluorobenzyl)-1H-indazole-3-acetic acid

A solution of methyl 1-(4-bromo-2-fluorobenzyl)-1H-indazole-3-acetate(0.30 g) in methanol (5 ml) containing 10% aqueous KOH (1 ml) wasstirred at room temperature for 16 hours. It was then concentrated to alow volume, and then diluted with ethyl acetate (10 ml) and sufficient10% HCl added to adjust the pH to about 4.0. The ethyl acetate layer waswashed with water (5 ml), dried and then evaporated to a white solid(yield: 0.21 g; m.p. 167°-168° C.).

By the same method, the other methyl and ethyl esters of the procedingExample were converted to:

1-[(5-(trifluoromethyl)benzothiazol-2-yl)methyl]-[1H-indazole-3-aceticacid (m.p. 168°-169° C.);

1-[(5-fluorobenzothiazol-2-yl)methyl]1H-indazole-3-acetic acid (m.p.173°-174° C.);

1-[(benzothien-2-yl)methyl]-1H-indazole-3-acetic acid (m.p. 164°-165°C.);

1-[(5-(trifluoromethyl)benzoxazol-2-yl)methyl]-1H-indazole-3-acetic acid(m.p. 204°-205° C.);

1-[(5,7-difluorobenzothiazol-2-yl)methyl]-1H-indazole-3-acetic acid(m.p. 168°-169° C.);

1-[(6-bromobenzothiazol-2-yl}methyl]-1H-indazole-3-acetic acid (m.p.186°-189° C.);

1-[(5-chlorobenzoxazol-2-yl)methyl]-1H-indazole-3-acetic acid (m.p.197°-198° C.);

1-[(3-(2-bromophenyl)-1,2,4-oxadiazol-5-yl)methyl]-1H-indazole-3-aceticacid (m.p. 208°-209° C.);

1-[(5-bromobenzothiazol-2-yl)methyl]-5-chloro-1H-indazole-3-acetic acid(m.p. 210°-211° C.);

1-[(5-chlorobenzoxazol-2-yl)methyl-5-chloro-1H-indazole-3-acetic acid(m.p. 227°-228° C.);

1-[(5-fluorobenzothiazol-2-yl)methyl-5-chloro-1H-indazole-3-acetic acid(m.p. 186°-188° C.); and

1-[(5-(trifluoromethyl)benzothiazol-2-yl)methyl-]5-chloro-1H-indazole-3-aceticacid (m.p. 189°-190° C.);

1-[(5,7-difluorobenzothiazol-2-yl)methyl]-5-chloro-1H-indazole-3-aceticacid (m.p. 196° C.).

EXAMPLE 4

By the methods of the preceding Examples 1-3, the following additionalcompounds are prepared from a suitably substituted 1H-indazole-3-aceticacid, or methyl or ethyl ester thereof, and a suitably substitutedbenzyl or (heteroaryl)methyl halide:

1-[(3-pyridyl)methyl]-1H-indazole-3-acetic acid;

1-[(4-methyl-2-pyridyl)methyl]-1H-indazole-3-acetic acid;

1-[(2-pyrrolyl)methyl]-5-methoxy-1H-indazole-3-acetic acid;

1-[(5-benzothiazolyl)methyl]-5-methyl-1H-indazole-3-acetic acid;

1-[(5-benzothiazolyl)methyl]-5-methoxy-1H-indazole-3-acetic acid;

1-(4-fluorobenzyl)-1H-indazole-3-acetic acid;

1-(3-methoxybenzyl)-1H-indazole-3-acetic acid;

1-(2,4-dimethylbenzyl)-1H-indazole-3-acetic acid;

1-[(1-isoquinolyl)methyl]-1H-indazole-3-acetic acid;

1-(2-thenyl)-1H-indazole-3-acetic acid;

1-furfuryl-1H-indazole-3-acetic acid;

1-[(4-thiazolyl)methyl]-1H-indazole-3-acetic acid;

1-[(3-isoxazolyl)methyl]-1H-indazole-3-acetic acid;

1-[(1-isoindolyl)methyl]-1H-indazole-3-acetic acid;

1-[(2-indolyl)methyl-1H-indazole-3-acetic acid;

1-[(3(1H)-indazolyl)methyl]-1H-indazole-3-acetic acid;

1-[(2-imidazolyl)methyl]-1H-indazole-3-acetic acid;

1-[(1,2,4-thiadiazol-5-yl)methyl-5-chloro-1H-indazole-3-acetic acid.

EXAMPLE 5 Pivaloyloxymethyl1-[(5-(Trifluoromethyl)benzothiazol-2-yl)methyl]-5-chloro-1H-indazole-3-acetate

Tetrabutylammonium hydrogen sulfate (0.374 g, 1.1 mmol) is dissolved in2.5 ml H₂ O. NaHCO₃ (92 mg, 1.1 mmol) is added portionwise at a ratewhich controls the foaming. Finally,1-[(5-trifluoromethyl)benzothiazol-2-yl)methyl]-5-chloro-1H-indazole-3-aceticacid (1.1 mmol) is added. After about 30 minutes of stirring, thesolution is extracted 4×5 ml CHCl₃ and the combined extracts are driedand stripped to yield the intermediate tetrabutylammonium salt. Undernitrogen, the latter is dissolved in 2 ml acetone and chloromethylpivalate (0.216 ml, 1.1 mmol) is added. After 24 hours, the acetone isstripped and the residue dissolved in 5 ml ethyl acetate, washed 3×5 mlwater and 1×5 ml brine, dried and restripped to yield title product,which, if desired, is further purified by chromatography on silica gel.

By the same method, substituting a molar equivalent of the appropriateorganic halide for chloromethyl pivalate, the following additionalesters are prepared:

furan-5(1H)-on-1-yl1-[(5-(trifluoromethyl)-benzothiazol-2-yl)methyl]-5-chloro-1H-indazole-3-acetate;

isobenzofuran-3(1H)-on-1-yl1-[(5-trifluoromethyl)benzothiazol-2-yl)methyl]-5-chloro-1H-indazole-3-acetate;

gamma-butyrolacton-4-yl1-[(5-trifluoromethyl)benzothiazol-2-yl)methyl]-5-chloro-1H-indazole-3-acetate;

1-(ethoxycarbonyloxy)ethyl1-[(5-trifluoromethyl)benzothiazol-2-yl)methyl]-5-chloro-1H-indazole-3-acetate.

EXAMPLE 6 2-Morpholinoethyl1-[(5-Bromobenzothiazol-2-yl)methyl]-5-chloro-1H-indazole-3-acetateHydrochloride

To the sodium salt of N-(2-hydroxyethyl)morpholine, prepared bycautiously adding sodium hydride (0.45 g; 50% w/w dispersion in mineraloil) to a solution of N-(2-hydroxyethyl)morpholine (1.43 ml) in toluene(50 ml), is added a solution of ethyl1-[(5-bromobenzothiazol-2-yl)methyl-5-chloro-1H-indazole-3-acetate (1.23g) in toluene (30 ml). After stirring at room temperature for 24 hoursand then at 60° C. for 6 hours, the reaction mixture is saturated withdry HCl gas. The precipitated solids are recovered by filtration, addedto saturated aqueous sodium bicarbonate (100 ml), and extracted withethyl acetate (3×100 ml). The organic layer is dried, evaporated and theresulting residue dissolved in acetone (30 ml). Saturation of thissolution with dry HCl yields the title compound.

EXAMPLE 7 2-(Morpholino)ethyl 1-(4-bromo-2-fluorobenzyl)-1H-3-acetate

Substituting the title product of Preparation 2 for the methyl1H-indazole-3-acetate, the method of Example 2 is used to preparepresent title product.

PREPARATION 1

Methyl 1H-indazole-3-acetate A solution of 1H-indazole-3-acetic acid(1.0 g) in methanol (30 ml) containing five drops of concentratedsulfuric acid was refluxed for 8 hours. It was then concentrated to alow volume, diluted with ethyl acetate (20 ml). The organic layer washedwith water (2×10 ml) and then with sodium bicarbonate solution (10 ml,10%). The ethyl acetate layer was collected and then dried to obtain thetitle compound (yield: 0.8 g; m.p. 146° C.).

The corresponding ethyl ester was prepared by substituting anhydrousethanol for methanol.

PREPARATION 2 2-(Morpholino)ethyl 1H-Indazole-3-acetate

By the method of Example 6, the title product of the preceding Exampleis converted to present title product.

We claim:
 1. A method of controlling chronic diabetic complicationswhich comprises administering to a mammal suffering from chronicdiabetes a chronic diabetic complication controlling amount of acompound of the formula ##STR11## wherein X¹ and X² are eachindependently hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C₁-C₃)alkyl or (C₁ -C₃)alkoxy;R is hydrogen or a racial group forming aconventional ester which is hydrolyzable under physiological conditions;X³, when taken separately, is hydrogen, fluoro, chloro, bromo,trifluoromethyl, (C₁ -C₃)alkyl, (C₁ -C₃)alkoxy or ##STR12## X⁴, whentaken separately, X⁵ and X⁶ are each independently hydrogen, fluoro,chloro, bromo, trifluoromethyl, (C₁ -C₃)alkyl or (C₁ -C₃)alkoxy; and X³and X⁴, when taken together, are combined with the adjacent carbons towhich they are attached to form a benzene ring substituted by X⁵ and X⁶; a pharmaceutically acceptable cationic salt thereof when R ishydrogen; or a pharmaceutically acceptable acid addition salt thereof.2. A method of claim 1 wherein R is:1H-furan-5-on-2-yl;1H-isobenzofuran-2-on-7-yl; gamma-butyrolacton-4-yl; --CH₂ CH₂ NR² R³ ;--CHR⁴ OCOR⁵ ; or --CHR⁴ OCOOR⁶ ; wherein R² and R³, taken separately,are each independently (C₁ -C₄)alkyl; or taken together with thenitrogen to which they are attached form a pyrrolidine, piperidine ormorpholine ring; R⁴ is hydrogen or methyl; R⁵ is (C₁ C₆)alkyl, (C₁-₆)carboxyalkyl, carboxycyclohexyl or carboxyphenyl; and R⁶ is (C₁-C₆)alkyl.
 3. A method of claim 1 wherein R is hydrogen.
 4. The methodof claim 3 wherein X¹ and X² are each hydrogen, X³ is 2-fluoro and X⁴ is4-bromo.